Submissions for variant NM_004360.5(CDH1):c.499G>A (p.Glu167Lys)

gnomAD frequency: 0.00003  dbSNP: rs769076258

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328266	SCV001943332	likely benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-10	reviewed by expert panel	curation	The c.499G>A (p.Glu167Lys) variant has also been observed in >10 (28) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000329225.7; SCV000259296.7). In summary, this variant meets criteria to be classified as likely benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206273	SCV000259296	likely benign	Hereditary diffuse gastric adenocarcinoma	2023-12-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000220446	SCV000275509	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-05	criteria provided, single submitter	clinical testing	The p.E167K variant (also known as c.499G>A), located in coding exon 4 of the CDH1 gene, results from a G to A substitution at nucleotide position 499. The glutamic acid at codon 167 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in individuals with personal and/or family histories of breast cancer (Tung N et al. J Clin Oncol. 2016 May 1;34(13):1460-8; Garcia-Pelaez J et al. Lancet Oncol, 2023 Jan;24:91-106). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000590271	SCV000329225	uncertain significance	not provided	2023-09-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal and/or family history of breast cancer and in an individual with mismatch repair (MMR) proficient colorectal cancer (Tung et al., 2016; Pearlman et al., 2021; Garcia-Pelaez et a., 2023); This variant is associated with the following publications: (PMID: 36436516, 22850631, 15235021, 34250417, 26976419)
Color Diagnostics, LLC DBA Color Health	RCV000220446	SCV000684465	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-15	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 167 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 26976419). This variant has been identified in 4/282610 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235127	SCV000698402	likely benign	not specified	2024-07-16	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.499G>A (p.Glu167Lys) results in a conservative amino acid change located in the cadherin-like domain (IPR002126) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.9e-05 in 1614014 control chromosomes, predominantly at a frequency of 2.5e-05 within the Non-Finnish European subpopulation in the gnomAD database (v4). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is higher than the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Breast Cancer phenotype (2.1e-05). c.499G>A has been reported in the literature in an individual affected with breast cancer without evidence for causality (Tung_2016) and in an individual affected with colorectal cancer (Pearlman_2021) who had a co-occurring pathogenic variant (MUTYH c.536A>G, p.Tyr179Cys), providing supporting evidence for a benign role. These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26976419, 34250417). ClinVar contains an entry for this variant (Variation ID: 219431). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl	RCV000206273	SCV000785428	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2017-07-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000206273	SCV001140133	benign	Hereditary diffuse gastric adenocarcinoma	2023-08-22	criteria provided, single submitter	clinical testing
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000206273	SCV003927048	likely benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BS2 (PMID: 30311375)
Myriad Genetics, Inc.	RCV000206273	SCV004019559	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-03-03	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003235127	SCV004242721	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing